This invention relates to methods for protecting stratified squamous epithelium against injury by noxious substances. This invention also relates to novel sulfate ester agents useful in these methods. Specifically, these methods and agents may be used in the protection and treatment of tissues damaged by or susceptible to damage by noxious substances such as acid, more particularly in the treatment of gastroesophageal reflux disease (GERD) arising from acid injury.
Gastroesophageal reflux (GER) is the effortless movement of gastric contents from the stomach to the esophagus. It is a physiologic process, occurring in everyone, many times a day throughout life and without symptoms or signs of tissue injury. However, beginning at about 35-40 years of age, GER is increasingly associated with the symptom of heartburn and morphologic injury to the esophagus. Indeed, a Gallup poll reported that up to 44% of adult Americans experience heartburn at least monthly and up to 10% have heartburn daily. The proximate cause for the transition from GER to gastroesophageal reflux disease (GERD) is the ability of noxious materials from the stomach to contact the esophagus with sufficient duration to result in damage to the epithelium. Moreover, it is well established that the major injurious agent within the refluxate is gastric acid, though the latter may be aided by the presence of pepsin within the refluxate.
The damage resulting from acid exposure can be demonstrated morphologically and/or physiologically by changes in potential difference (PD), electrical resistance (R), or permeability to ions and molecules (Chung, R. S., et al. Am. J. Physiol. 229(2): 496-500, 1975; Dodds, W. J., et al. Invest. Radiol. 5: 209-219, 1970; Harmon, J. W., et al. Dig. Dis. Sci. 26: 65-72, 1981; Kidder, J. W., et al. J. Lab. Clin. Med. 102: 477-486, 1983; Kivilaakso, E., et al. Surgery 87: 280-285, 1980; Salo, J., et al. Surgery 92: 61-68, 1982).
The pathophysiology of acid injury has been most thoroughly explored using the rabbit esophageal epithelium as a model for the human esophageal epithelium. Both human and rabbit esophageal epithelia are Na+-absorbing xe2x80x98electrically-tightxe2x80x99 stratified squamous epithelia. Each junctional complex consists of tight junctions with a few strands and an intercellular glycoprotein matrix. Moreover, rabbit and human esophageal epithelia both respond to high luminal acidity with a time-dependent biphasic change in transepithelial PD. Further, individual squamous cells utilize a basolateral membrane, acid-extruding, Na+/H+ exchanger (NHE-1 isotype) as a principal mechanism for regulation of intracellular pH (pHi) (Orlando, R. C., et al. In: Castell, D. O., et al., eds. The Esophagus (3 rd Edition). Philadelphia: Lippincott Williams and Wilkins, 1999, 409-419, and Orlando, R. C., et al. In: Orlando, R. C., et al., eds. Gastroesophageal Reflux Disease. Marcel Decker, in press).
Key observations in humans that support a similar pathogenesis for acid reflux-induced injury to human esophageal epithelium as defined in the rabbit model are: 1) luminal perfusion in vivo with high concentrations of HCl (Bernstein test) produces a similar biphasic pattern in esophageal PD (Orlando, R. C., et al. Am. J. Med. 108: (4A): 104S-108S, 2000, and Orlando, R. C., et al. In: Allen, A., et al., eds. Mechanisms of Mucosal Protection in the Upper Gastrointestinal Tract. New York: Raven Press, 1984, 75-79); and, 2) patients with both erosive and nonerosive GERD have the same morphologic hallmark of early acid damage to esophageal epithelium, i.e. dilated intercellular spaces. Tobey, N. A., et al. Gastroenterology 111: 1200-1205, 1996.
Previous work has shown that sodium sulfate has a cytoprotective effect in acid exposed rabbit esophagus (Tobey, N. A., et al. Am. J. Physiol. 251 (Gastrointest. Liver Physiol. 14): G866-G869, 1986). In U.S. Pat. Nos. 5,374,537 and 5,189,056 it was alleged that protection of stratified squamous epithelia against damage from noxious luminal agents, e.g. HCl, was afforded by chemical compounds having one of the following reactive groups in their molecule: Xxe2x80x94SO3xe2x88x92, where X represents oxygen or carbon, and XO4= or X2O7=, where X represents an element from Group VIb of the periodic table or sulfur. The compounds which were shown to provide protection against injury to stratified squamous epithelia included 4-acetamido-4xe2x80x2-isothiocyano-2,2xe2x80x2-stilbene disulfonate (SITS), 8-anilino-naphthalene-1-sulfonate (ANS), dinitrodisulfonic acid stilbene (DNDS), sulfonazo III, 4,4xe2x80x2-diisothiocyano-2,2xe2x80x2-stilbene disulfonate (DIDS), bromophenol blue, ethane disulfonate, 1,3-benzene disulfonate, sucrose octasulfate (SOS), dextran sulfate, sodium chromate, sodium dichromate, sodium molybdate, sodium tungstate and sodium sulfate. Labeaga et al. disclose dosmalfate as a gastrointestinal and esophageal cytoprotective agent (Labeaga, L. et al. Drugs of Today 2000, Vol. 36, Suppl. A: 59-66, 2000).
There is a continued need for methods and agents for treating gastroesophageal reflux disease (GERD) and other conditions associated with the exposure of stratified squamous epithelial tissue to noxious substances.
All references cited herein are hereby incorporated by reference in their entirety.
The present invention provides a method for protecting stratified squamous epithelium against injury by a noxious substance comprising contacting the epithelium with an effective amount of an agent comprising a) at least one aromatic group; b) at least one xe2x80x94OSO3R4 moiety, wherein R4 is H or a pharmaceutically acceptable cation; and c) at least one xe2x80x94NCS, xe2x80x94NCO, xe2x80x94NH(CO)xe2x80x94OR3, xe2x80x94NH(CS)SR3, xe2x80x94NH(Cxe2x95x90NH)OR3, xe2x80x94NHCOCH2Cl, xe2x80x94NHCOCH2Br, xe2x80x94NHCOxe2x80x94CHxe2x95x90CH2, or xe2x80x94NHC(O)xe2x80x94CF3 moiety.
In another aspect of the invention, the present invention provides novel compounds and a method for protecting stratified squamous epithelium against injury by a noxious substance using the novel compounds comprising administering to the epithelium an effective amount of an agent comprising: 
wherein: X is a linker selected from the group consisting of C1-C6 alkylene, C2-C6 alkenylene, or C3-C6 alkynylene, wherein X may optionally include 1 or 2 oxygen atoms and/or 1 sulfur atom; Y is a group pendant from X comprising at least one xe2x80x94OSO3R4 moiety, wherein R4 is H or a pharmaceutically acceptable cation; n is an integer from 1-3; and R1 and R2 are each independently selected from the group consisting of xe2x80x94H, a halogen with an atomic number from 9 to 53, hydroxy, xe2x80x94SO3R4, xe2x80x94OSO3R4, xe2x80x94NCS, xe2x80x94NCO, xe2x80x94NH(CO)xe2x80x94OR3, xe2x80x94NH(CS)SR3, xe2x80x94NH(Cxe2x95x90NH)OR3, xe2x80x94NHCOCH2Cl, xe2x80x94NHCOCH2Br, xe2x80x94NHCOxe2x80x94CHxe2x95x90CH2, xe2x80x94NHC(O)xe2x80x94CF3, xe2x80x94Sxe2x80x94CH2xe2x80x94CHxe2x95x90CH2, xe2x80x94NHCH2xe2x80x94Cxe2x95x90CH, xe2x80x94NHxe2x80x94CH2xe2x80x94CN, xe2x80x94NHxe2x80x94Sxe2x80x94CH2xe2x80x94CHxe2x95x90CH2, xe2x80x94Oxe2x80x94CH2xe2x80x94CHxe2x95x90CH2, xe2x80x94NHxe2x80x94CF3, N-mono-, di-, tri-, tetra- and penta-haloethyl, xe2x80x94CN, xe2x80x94NH2, xe2x80x94NO2, xe2x80x94NHCOCH3, xe2x80x94CHO, xe2x80x94COOR4, xe2x80x94N3, xe2x80x94COR3, xe2x80x94R3OH, xe2x80x94R3NHCOCH3, xe2x80x94R3OSO3R4, xe2x80x94R3 SO3R4, xe2x80x94OR3, xe2x80x94SR3 and xe2x80x94R3, wherein R3 is p-nitrophenyl, C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl, if at the distal end of the substituent, or C1-C6 alkylene, C2-C6 alkenylene, or C2-C6 alkynylene, if at the proximal end of the substituent, and wherein R4 is H or a pharmaceutically acceptable cation.
In another aspect of the invention, kits for treating an individual who suffers from or is susceptible to gastroesphageal reflux disease (GERD), heartburn, laryngitis, and pharyngitis are provided comprising a) a container comprising a dosage amount of an agent or composition as disclosed herein; and b) instructions for use.